Guide the immune system to fight cancer

CancerCells by dream designs (ID-100279675)While the primary interest in EPICentre is on cancer research related to prevention and early detection, we do have a keen interest in progress related to novel cancer treatments, and in the last few years there have been important developments in immunotherapy. Immunotherapy is a relatively new form of treatment to ‘wake up’ a patient’s own immune system to fight cancer. The challenge is that cancers are often made up of differentiated cells, characterized by a heavy load of genetic mutations. Cancer cells can look and behave very differently, even within a tumour. So far, immunotherapy treatments have been powerful-but-blunt weapons, in the sense that they have not been very specific to relevant tumour cells, even resulting in potentially serious side effects.

Lately, immunotherapy has received growing attention from cancer research professionals and worldwide media. A powerful element of immunotherapy is that engaging the immune system against cancer might have long-lasting benefits, if the immune system can ‘remember’ the cancer and stop recurrence. In this blog item, we take a closer look at recent evidence produced by researchers at University College London (UCL) and the Francis Crick Institute (FCI) who joined forces to carry out a Cancer Research UK funded study to develop a way to identify unique markers within a tumour to help the immune system to better target cancer cells.(1) How does it work? 

Virtually all cells in the body display samples of the proteins they produce on their surface. These small samples are called antigens, substances that cause the immune system to produce antibodies directed against them. Antigens act as ‘flags’ for the immune system. During tumour development, when a cell becomes damaged, it starts changing the proteins it produces, thus displaying new antigens on its surface. Specialized immune cells, called T-cells, can then spot these antigens, releasing signals that destroy the damaged cell. Once the immune system recognizes cancer-specific antigens, cancer cells that carry that flag are destroyed.

But here is where the problem arises. During cancer development the DNA faults inside the cell can also change the way antigens ‘look’ to the immune system. In this way the tumour blocks the reaction of the immune system. Tumour cells progressively grow like a tree carrying over core “trunk” mutations that can persist late in its development. The mutations branch off in many directions, thus creating tumour cells differentiation, also known as cancer heterogeneity. UCL and FCI researchers set up an international study to discover the “trunk” mutations, the ones responsible for changing the antigens. The diversity of mutations observed in tumour evolution would be reflected by the antigens present on the cancer cells, thus allowing the identification of target antigens.

To test this, they turned to The Cancer Genome Atlas (TCGA), which records genetic data on thousands of cancer patients, alongside how they fared after treatment. They compared data from over 200 patients with one of two different types of lung cancer (adenocarcinoma and squamous cell carcinoma) to information from TCGA.  They subsequently predicted how many antigens a tumour contained, and the proportion that were common throughout the tumour. Three common antigens were identified, each of them was predicted to be present on every cancer cell in the tumour sample. In addition, they observed that tumours containing many antigens shared across the cancer cells produced high levels of an immune-dampening molecule called PD-L1. The team then looked at data from patients in a US study, who received a checkpoint immunotherapy drug called pembrolizumab (Keytruda), which blocks the immune cells from receiving the PD-L1 ‘stop signal’. Tumours attracted immune cells, which were suppressed by the cancer cells to stay alive. But if specific drugs to break through the cancer’s defence were given to patients, they responded well to treatment.

The work suggests two possible routes to treat cancer patients. One strategy could be to take a biopsy from a patient’s tumour, read its genome and work out which flags (antigens) are present on all of the malignant cells. If there are immune cells inside the tumour that recognize these flags, they could be multiplied in the lab, and then re-infused into the patient, producing an overwhelming precision attack on the cancer cells. In another scenario, the protein flags themselves could be used to make a vaccine against the cancer. Inject them into the body, and immune cells would identify them as invaders and launch an attack. The new therapies would have to be used alongside existing drugs called “checkpoint inhibitors” that stop cancers neutralising T-cells.

A successful immunotherapy will be the one that harnesses the immune system to recognize the type of antigens. Experimental treatments that simply show any antigen to the immune system will not necessarily be useful. It has been argued that any treatment for an individual patient will be extremely expensive and laborious to implement except in very special circumstances. The real hope would be to identify immunotherapy targets that can tackle groups of cancer provided that projects like The Cancer Genome Atlas produce some finer molecular classifications of tumours. There is clearly a long way to go for this evidence to be translated into effective large scale cancer care.

(1) Reference: McGranahan et al., Science, 2016. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. PMID: 26940869.

Pietro Ferrari

Pietro Ferrari

Pietro Ferrari is a statistician working in the Nutritional Epidemiology Group at the IARC in Lyon, France. He has been long involved in the EPIC study, and his research covers aspects related to Nutritional Epidemiology. These include evaluations of dietary exposure misclassification, technique for bias correction in exposure disease models, competing risks modelling, analysis of complex sets of data involving dietary, lifestyle and biomarker measurements, modelling of metabolomics and epigenetic data.
Pietro Ferrari

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